The dramatic improvement in neonatal care during the last decade did not succeed in reducing the incidence of periventricular leukomalacia (PVL), suggesting that prenatal events may be the main target for PVL prevention. The studied cohort included 753 very preterm infants born between 24 and 32 weeks of gestational age, admitted to the intensive care unit and surviving at least 7 days; 69 (9.2%) of these infants had a diagnosis of cystic PVL. The highest PVL frequency was observed among the infants born at 28 weeks of gestation (16%). Inflammatory prenatal events occurring during the last days or weeks before delivery and PVL occurrence are strongly correlated. Indeed, the combination of intra-uterine infection and premature rupture of membranes is associated with a very high risk (22%). Prolongation of pregnancy with tocolysis for more than 24 hours also carries a significant 8% risk of PVL. In contrast, chronic fetal distress of long duration, such as severe intra-uterine growth retardation and pre-eclampsia, is seldom followed by PVL (< 2% risk). Similarly, rapid unexpected deliveries entail a minimal PVL risk (4%). Experimental and epidemiological confirmations of these data would have an influence on the management of both the preterm onset of labour and the premature rupture of membranes.